The context-dependent role of Caveolin-1 as a driver of cellular adaptation in Ewing Sarcoma

Caveolin-1 作为尤文肉瘤细胞适应驱动因素的背景依赖性作用

• 批准号: 10662162
• 负责人: Dagan Segal
• 金额: $ 15.16万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662162
• 关键词: Acute; Area; Biochemical; Biological Assay; Biology; Biosensor; Bone Tissue; Cancer Biology; Cancer Model; Cell physiology; Cells; Childhood; Chimeric Proteins; Classification; Clinical Treatment; Computer Analysis; Computer Vision Systems; Cues; Data; Development; Disease Progression; Disease model; Drug resistance; Environment; Evolution; Ewings sarcoma; Experimental Models; Explosion; Flow Cytometry; Foundations; Gene Expression; Genetic; Heterogeneity; Image; Knock-out; Laboratory Study; Lead; MAP Kinase Gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mechanics; Membrane; Microscopy; Modality; Modeling; Molecular; Molecular Target; Morphology; Mutation; Neoplasm Metastasis; Oncogenic; Organizational Change; Osmotic Pressure; Pathway interactions; Pattern; Physiological; Postdoctoral Fellow; Process; Proliferating; Ras Signaling Pathway; Regulation; Resources; Role; Scaffolding Protein; Signal Transduction; System; Techniques; Testing; Three-dimensional analysis; Time; Training; Tumor Promotion; Work; Xenograft procedure; Zebrafish; biological adaptation to stress; cancer cell; cancer type; caveolin 1; differential expression; extracellular; functional plasticity; high resolution imaging; imaging approach; innovation; insight; knock-down; mechanical force; mechanical signal; neoplastic cell; non-genetic; overexpression; post-doctoral training; response; segregation; skills; soft tissue; spatiotemporal; three dimensional cell culture; trafficking; tumorigenesis

Project Summary My work aims to uncover non-genetic mechanisms that drive cancer cell plasticity. I focus specifically on Ewing Sarcoma, a pediatric cancer driven by a single oncogenic fusion, making it prototypical for cancers whose disease progression likely depends on non-genetic adaptations. During my postdoc thus far, I have developed two complimentary models to study heterogeneity of cell states in Ewing Sarcoma: (1) a quantitative high- resolution imaging assay that uses computer-vision based classification of single cell states within Ewing Sarcoma xenografts in zebrafish, and (2) a bimodal distribution of cell signaling states characterized by differential expression and organization of the scaffolding protein Caveolin-1. While the precise role of Caveolin- 1 in cancer remains controversial, recent works suggest that mechanical cues trigger changes in its localization and activity, implicating Caveolin-1 as a potential integrator of environmental cues and cell signaling. However, the mechanism of response and the ensuing signaling cascades remain to be understood, especially in the context of cancer. Therefore, I will leverage the unique experimental frameworks I have established to test whether Cav-1 acts as a plasticity factor promoting tumor cell adaptation in Ewing Sarcoma. This work will reveal mechanisms of fast cellular adaptation to diverse microenvironmental cues which will provide unique insight into the drivers of metastasis and drug resistance. I am eager to build upon the foundations I have established during my postdoc thus far to discover previously unapproachable mechanisms of cell adaptation. As the proposed work requires cross-disciplinary expertise, my continued development in several areas will be instrumental to my progress. Dr. Danuser and the Danuser lab will provide the ideal environment to develop advanced microscopy techniques and skills in computational analysis of 3D data. Dr. Amatruda will provide guidance and support in the use of zebrafish disease models and relevance to pediatric cancer. Dr. Lamaze and Dr. Cobb will provide scientific insight in caveolar biology, MAPK cell signaling, and cancer biology. Combined with the stellar training environment and resources available at UT Southwestern, this provides the ideal environment to carry out this work. The training I will receive will enable me to lead an independent laboratory that studies cancer cell plasticity in a variety of experimental models, with specific focus on imaging-based approaches and physiologically relevant environments.

项目摘要 我的工作旨在揭示驱动癌细胞可塑性的非遗传机制。我特别关注尤因 肉瘤，一种由单一致癌融合驱动的儿科癌症，使其成为癌症的原型， 疾病进展可能取决于非遗传适应。到目前为止，在我的博士后期间，我开发了 两种研究尤文肉瘤中细胞状态异质性的互补模型：（1）定量高- 使用基于计算机视觉的尤文内单细胞状态分类的分辨率成像测定 斑马鱼中的肉瘤异种移植物，和（2）细胞信号传导状态的双峰分布，其特征在于 支架蛋白Caveolin-1的差异表达和组织。而小窝蛋白的确切作用- 1在癌症中仍然存在争议，最近的工作表明，机械线索触发其定位的变化 和活性，暗示Caveolin-1作为环境线索和细胞信号传导的潜在整合者。然而，在这方面， 反应机制和随后的信号级联仍有待了解，特别是在 癌症的背景。因此，我将利用我建立的独特的实验框架来测试 Cav-1在尤文肉瘤中是否作为促进肿瘤细胞适应的可塑性因子。这项工作将揭示 快速细胞适应不同微环境线索的机制，这将提供独特的见解， 转移和耐药性的驱动因素。 我渴望建立在我在博士后期间建立的基础上，迄今为止， 细胞适应的不可接近的机制。由于拟议的工作需要跨学科的专业知识，我 在几个领域的持续发展将有助于我的进步。Danuser博士和Danuser实验室 将提供理想的环境，以发展先进的显微技术和技能，在计算 3D数据分析。Amatruda博士将在斑马鱼疾病模型的使用方面提供指导和支持， 与儿科癌症的相关性拉梅兹博士和科布博士将提供科学的见解，在小窝生物学，MAPK 细胞信号和癌症生物学。结合UT的一流培训环境和可用资源 西南部，这提供了理想的环境，开展这项工作。我将接受的培训将使 我将领导一个独立的实验室，在各种实验模型中研究癌细胞的可塑性， 特别关注基于成像的方法和生理相关环境。